Friday, April 3, 2009

The Locus Coeruleus and autism

I just thought that I would have to comment on the new study that implicates the area of the brain known as the locus coeruleus with autism. The locus coeruleus is the source in the brain of the neurotransmitter norepinephrine. The hypothesis originates from the fact that there is anecdotal evidence that when autistic children get fevers this mitigates their symptoms. The locus coeruleus is involved in fever. The authors go on to speculate that autism could just be due to dysregulation of the locus coeruleus and because of this it could make it easier to mitigate the symptoms of autism or possibly even find a way to reverse it. I have only read the article in science daily that I have linked to and the abstract of the study, so I can't comment on all of the specifics of the study. From what I have read though it sounds more like a hypothesis than the authors having any empirical evidence that the LC plays any role in autism. So, I won't hold my breath as far as any major breakthroughs in the treatment of autism as a result of this research. However, when reading things like this, it helps to give hope that someday, something can be done to mitigate or cure this horrible tragedy that afflicts so many persons. The authors go on to emphasize in the article that this does not mean something can be done for autism as a result of their research in one fell swoop (their words).

If the prevalence of autism is really 1 in 150, then if this becomes more than a hypothesis and further research validates this as something that could help autism, then this would provide an incentive for drug companies to come up with some norepinephrine agonist (a drug that will create more norepinephrine in the brain presuming autism is caused by a dysregulation of this neurotransmitter) and much money would be made and autism at the very least would be as treatable as schizophrenia is currently with anti-psychotic medications even if the medications don't cure autism. This might make ABA as a therapy for autism just as obsolete as hydrotherapy is now for schizophrenia. Hydrotherapy was the treatment of choice for schizophrenia in the 1940s before anti-psychotic medications were developed and used for schizophrenics. Like ABA, its proponents touted hydrotherapy as the only scientifically proven treatment to ameliorate schizophrenia. I realize that these are just dreams now and it is unlikely such a medication or treatment for autism will be invented based on this research in the foreseeable future.

I have emailed the lead author of the study Dr. Mehler and have asked him for a .pdf copy of the actual study itself so I will have more to read than just the science daily article and the abstract. If I get the actual paper I may edit this post or post a follow-up post.

What is most interesting of all to me is that about 20 years ago, when I had my first MRI scan by Eric Courchesne's research group, I had a similar speculation that the etiology of autism might be caused by a dysfunction in the locus coeruleus and that norepinephrine might be involved in the etiology of autism. The dorsal tegmental bundle is a tract that comes from the locus coeruleus and is one of the two main tracts of neurons that spreads the neurotransmitter norepinephrine to the various areas of the brain that use this substance to generate chemical messages that control various functions of the brain. The axons of these fibers project to the neocortex, hippocampus and cerebellar cortex and medulla. The cerebellum has been implicated in autism and various studies have shown a loss of purkinje cells in the cerebellum of autistics as opposed to normal controls. Norepinephrine is one of the two neurotransmitters that are used by purkinje cells The other one is GABA (gamma amino butyric acid). Norepinephrine acts as an inhibitory neurotransmitter. This might be the reason for the inability to control certain movements in autism and "stimming", lack of an inhibitory neurotransmitter. More evidence of the norepinephrine/stimming theory comes from the fact that some of the axons of the dorsal tegmental bundle terminate on the superior cerebellar peduncle, which is one of the three structures that attach the cerebellum to the rest of the brain. It has been found that stimulation of the superior cerebellar peduncles is reinforcing. Subsequent studies have found ablation of the locus coereulus did not abolish this reinforcing effect. I think it is possible that norepinephrine in the typical brain acts as an inhibitory neurotransmitter and suppresses certain things in the superior cerebellar peduncle. If this system was dysregulated it could cause lack of inhibition causing autistics to self-stimulate in order to get this reinforcement.

As I mentioned before, these fibers also travel through the hippocampus. This brain structure is responsible for short term memory. Persons who have had severe epileptic seizures have sometimes had this brain structure removed. These persons can no longer form short term memories and they constantly live in the past. I wrote a short story that was inspired by this phenomena.

Various studies have found abnormalities in the limbic systems of persons with autism. The hippocampus is part of the limbic system. Also persons with autism often have extremely good memories. Some of them are even savants with photographic memories. It is possible that the lack of an inhibitory neurotransmitter such as norepinephrine could produce this effect, opening up structures that would be normally inhibited in a typical brain.

I discussed this theory with Eric Courchesne at the time I was his research subject and he said it was an interesting theory that could possibly be valid, but only science would be able to tell. I wondered if it would be possible to do an MRI scan of the cerebellar peduncles the way he had scanned the cerebellum and had found abnormalities in the cerebellar vermi of persons with autism. He stated that such a study could not be done because the cerebellar peduncles were only a few millimeters and too small to be measured with MRI scanning and compared to typical controls. Of course this was many years ago and things may have changed so it might be possible to do a structural MRI of this area of the brain now. Of course, most studies nowadays seem to be doing functional MRI rather than structural.

I wrote to Margaret Bauman, another autism researcher, and asked her if there was evidence of abnormalities in norepinephrine in autistic brains. She stated that her research had not found any but it was possibly due to the measurement techniques they used.

Dr. Bauman is one of the few persons to have done post mortem autopsies of the brains of persons with autism. It would be good if post mortem autopsies could be done but the problem is autistics usually live out their natural lives and it has been only recently that persons have been diagnosed as autistic. This does not mean that autistics over the age of 75 do not exist as the mercury militia and others insist, but only that they were never diagnosed. If such persons near the end of their life could be found and will their brains to science, then perhaps we could find some real answers to autism and possibly even a cure someday. Of course I realize this is not realistic anytime in the foreseeable future.


SM69 said...

Yeap, I saw this report earlier this week but have not yet read the study- one thing came to my mind right away when this was mentioned, that is of course, that although yes some kids with autism improve with fever, it is by no mean all of them (this has been reported maybe in 20 of 300 kids I have seen, at most, I do not know for sure on the top of my head). And unlike what was stated in the news report, no one could ever claim that these improvements equal to recovery, who would test autism rigorously in a child who has fever anyway? That’s just unethical. Also, generally speaking these kids also present with clear indication of latent infection and a better explanation relate to the improvement of their immune system with fever (which is we should remember a natural healthy good response to infection- many of our kids do not develop fever when they have an infection). I think this is much more of a theory than any of the other issues you have discussed in your post, but one should always consider ideas as a matter of principle. Regarding the imaging brain studies you brought in your psot, you need to keep in mind the incredible disparities in both structural and functional imaging findings obtained so far- the only consensus is that they don’t agree and virtually nearly every part of the brain has been implicated one way or another in autism, prefrontal, temporal, parietal, cortex yes the limbic system, the cerebellum, and even the brain stem. Also, many studies have found little brain abnormalities that could be detected with the techniques used. There are a few post-mortem studies in children dying accidentally, the most impressive one in my opinion is from Vargas 2005, it shows some abnormalities in the cortex and in the cerebellum with loss of Purkinje cells, but most of all the most dramatic differences found were in the levels of inflammatory cytokines with 200 fold increase for IFN-gamma (interferon gamma) for example and activation of microglia (also relating to inflammation). A whole bunch of immune markers and growth factors were tested in that study. It is very elegant. There are also studies coming up that suggest that in cases of regression, there is acute demyelination (seen by MRI scan and also with the presence of antibodies against Myelin basic protein) and that these abnormalities resolve after the acute phase of deterioration of function. It is possible that even within individuals, there are temporal longitudinal variations.

Well that post contrasts with the poem I sent earlier on! I can share references /papers for the very keens.

Jake Crosby said...

Hi Jon, what do you think of this study by Penn researchers linking autism to vasoconstriction and subsequent oxidative stress on the brain?

jonathan said...

hi jake, i checked out that link, but the server won't let me read that file.

Jake Crosby said...

Sorry about that, here's the text, if your search "autism" "penn" and "vasoconstriction" you should be able to find the original page...

AUGUST 15, 2006
Penn Researchers Find Link Between Autism and Abnormal Blood-Vessel Function and Oxidative Stress
New Findings Could Help Explain Pathology of Autistic Syndrome
(Philadelphia, PA) - Researchers at the University of Pennsylvania School of Medicine discovered that children with autism showed signs of abnormal blood-vessel function and damaging levels of oxidative stress compared to healthy children. The children with autism possessed levels of biochemicals that indicate the presence of constricted blood vessels via the endothelium (the cells that line vessels) with a higher tendency to form clots (through cells called platelets).

By exploring the relationship between oxidative stress and blood-vessel function in autistic patients, investigators hope to find new therapeutic options for this syndrome. The researchers, led by Domenico Pratico, MD, Associate Professor of Pharmacology, published their findings in the August issue of the Archives of Neurology.

According to the Autism Society of America, the reported number of autism cases is increasing 10 to 17 percent per year in the United States. Autism, an early onset neurological disorder, is characterized by impaired social interactions, limited verbal and nonverbal communication, and repetitive and restricted behavioral patterns. Patients with autism can differ in the severity and scope of their symptoms, suggesting that multiple factors contribute to explaining the disorder’s symptoms. Previous studies at other institutions have shown that autistic patients have reduced cerebral blood flow, presumably due to constricted blood vessels in the brain, versus healthy controls.

Urinary samples of autistic children who were similar in age and healthy controls were provided by the Pfeiffer Treatment Center, where patients were diagnosed with autism disorder and evaluated. Patients were excluded from analysis if they had ever received anti-oxidant treatments or medicine with any known anti-oxidant effect; if they suffered from chronic illnesses, such as depression, psychosis, or inflammatory disorders; and/or if they were sick at the time of the sample collection. These strict criteria resulted in the small sample size in this preliminary study: 26 children with autism and 12 healthy controls.

Pratico’s team measured isoprostane, a biomarker for oxidative stress; thromboxane, an index of platelet activation; and prostacyclin, a measure of blood vessel activation in the samples. “This study represents the first observation that the rates of thromboxane and prostacyclin synthesis are both not only significantly increased in autism, but are closely correlated with the rate of oxidative stress,” says Pratico. Compared with controls, children with autism had significantly higher urinary levels of isoprostane, thromboxone, and prostacyclin.
Oxidative stress is the result of an excessive formation of chemically unstable byproducts, called free radicals, within the cell. Under normal conditions, the cell is able to destroy the free radicals. However, when excessive free radicals accumulate, these molecules mount an attack against the cell in search of chemical stability.

“During oxidative stress, it is as if the free radicals have only one leg,” explains Pratico. “They are searching for the second leg in order to keep from falling. Unfortunately, the ability of the excessive free radicals to reestablish their chemical equilibrium comes always with a price for the organ -- irreversible cellular and organ damage.” Free radicals can damage cell membranes, proteins, and genes by oxidation -- the same chemical reaction that causes iron to rust.

Pratico and colleagues measured levels of isoprostane, the chemical byproduct of free radicals attacking fat cells and found that patients with autism possess nearly double the level of oxidative stress than that measured in healthy controls.

The samples from autistic patients also revealed a biochemical imbalance in the patients’ blood vessels, resulting in high levels of thromboxane - an indicator of platelet activity - and prostacyclin, an indicator of constricting endothelial cells. During normal function, thromboxane and prostacyclin work together to maintain the integrity of vessels. In response to different kinds of stress, platelets release thromboxane, which causes vessels to contract. The endothelium responds to elevated levels of thromboxane by releasing prostacyclin. This event counterbalances the effect on vessels, inducing dilation of the vessel and, in turn, more blood flow.

Autism is a complex neurological disorder and oxidative imbalance is one feature of the autistic syndrome. Several lines of evidence support the hypothesis that oxidative imbalance may also play a role in this disease: autism is characterized by an impaired anti-oxidant defense system, higher free-radical production, and improvement of behavioral symptoms after taking anti-oxidants.

“In general, it is known that abnormalities in blood vessels can be clinically reflected by an abnormal blood flow,” says Pratico. “In this regard, it is interesting that earlier neuroimaging studies of autistic children have demonstrated a reduced amount of blood reaching the brain. Shedding more light on the relationship of oxidative stress and blood-vessel health to the pathology of autism could lead to improvements in therapy.”

Study co-authors are Yuemang Yao from Penn; William J. Walsh, Pfeiffer Treatment Center (Warrenville, IL); and Woody R. McGinnis, Oxidative Stress in Autism Initiative (Ashland,OR). The research was supported in part by the Pfeiffer Treatment Center.

jonathan said...

well that is an interesting study, don't really have a comment on it, other than I am more interested in specifically what brain areas are affected in autism. I was interested in posting about the locus coeruleus because i had that theory for a long time.

Of course, now it seems the most widely replicated findings are in mirror neuron dysfunctions in the frontal and parietal lobes. I may blog about that in the near future.

bullet said...

Well, from personal experience Tom has just come down with chicken pox. He is itching, feverish and downright miserable. There is absolutely no mitigation of his autism.

Jake Crosby said...

Well Jon, problems with the locus coerulus would definitely explain our problems with executive functioning, however it would not explain our problems pertaining to communication, but those of the frontal and pariental lobes would which is probably explained by cerebral vasoconstriction.

Anonymous said...

"Well Jon, problems with the locus coerulus would definitely explain our problems with executive functioning"

Jake, the inability to properly footnote is not necessarily an executive functioning issue and based on your statements that you don't require any accommodations, I don't believe you have executive functioning issues.

SM69 said...

Hi Jake

Thanks for flagging this study- I measure the same markers in the urine and have the same findings (collecting data as we speak to look at ASD population level), isoprostane, but also 2 others markers that results form oxidative damage to DNA and RNA. The results are very interesting as these markers correlate with others, neopterine, a merker of cell-mediated immunity (meaning immune system is activated), and also often, but not always elevated porphyrins, particularly pre-coproporhyrin (mercury related porphyrin). The profile is very tight, that’s possibly the most interesting tools we have at the moment as initial screen to sub-categorize the kids, all in the urine and pretty inexpensive to run. Oxydative stress/ inflammation is very very common in autism.

SM69 said...

An interesting article that explains epigenetic, it should be apparent as to why this is very relevant to autism.

In my opinion autism is a condition with altered integration between systems, between brain regions, between the brain and the periphery and the CNS and there are many way to impede that integration. (This is a view shared by others like Martha Herbert). That could explain why there is no consensus about specific brain regions implicated, specific genes, or specific trigger. I have seen people without a diagnosis of autism behaving in very autistic ways because some of their senses are affected for example deftness, also, there are co morbidity of autism with several genetic conditions- which are totally unrelated in term of etiology, same is true of some infectious disease contracted at critical time of development . Finally, I think anyone can behave in an autistic way under certain circumstances, being an illness, being an intense emotional trauma, being a sensory overload.

Anonymous said...

I was forwarded an article about this topic the other day, only the source I received came from an online science blog.

Oh, I'd love it if there was a way the neurons stuck together in a bundle in the Locus Coeruleus could be seperated and migrated to the proper brain regions so me and the other 'sheltered' autistics (ND folks especially seem to enjoy being sheltered and likely don't get outside their houses much) could be free of this curse!

When I was little, I actually did feel a bit hyperactive whenever I'd get a fever at times (really stimming and wanting to play video games- really the same one(s) I had playing for a while...whatever game(s) I was focused on and enjoyed playing at the time of my fever). My mom would wonder if I should have gone to school whenever the middle to the end of the first day or second, or usually third day coming off a fever if I should have attended school instead of deciding to stay home.

I never enjoyed taking a nap until I got older and depressed and insecure due to having repressed some things due to no one understanding my co-morbid problems that come along with my autism and from sensing I knew all along I've been living with brain dysfunction glitches that turn out they have needed 're-wiring' for years, only no one else or myself really ever thought it was because I needed to see a speech-language pathologist who specializes in dealing with those on the autistic spectrum and other disabilities who've gained speech and language regardless of having had speech therapy as a child. No one could ever understand where I was coming from (or could they have in reality?) despite dealing with some of the smartest people online.
Half of them thought I was annoying after a while even though they were the ignorant ones.

Oh well! It's the Internet!

SavedAspie said...

Wow, I was just going to blog on this article, but seems you and your commenters have all my major points covered ;-)